Ribonucleases are proteins which catalyze the hydrolysis of phosphodiester bonds in RNA chains. They have similar primary structures and catalytic mechanisms. The RNA bonds hydrolyzed are ones between phosphorus and 5' oxygen atoms, generating a free 5'-OH group and a free 3'-phosphate group as new termini. The hydrolysis proceeds through an essential 2',3'-cyclic phosphate intermediate unique to RNA sequences. Although ribonucleases also have affinity for DNA sequences, hydrolysis does not occur because DNA lacks a 2'-hydroxyl group important for the formation of the 2',3'-cyclic phosphate intermediate. Four disulfide bonds, two histidine residues, and one lysine residue are highly conserved among ribonucleases and are important for catalysis.
Ribonucleases have evolved to support a variety of other physiological activities in addition to their function in hydrolysis of RNA. Such activities include anti-parasite, anti-bacterium, anti-virus, anti-neoplastic activities, neurotoxicity, and angiogenesis. For example, bovine seminal ribonuclease is anti-neoplastic (Laceetti, P. et al. (1992) Cancer Res. 52: 4582-4586). Some frog ribonucleases display both anti-viral and anti-neoplastic activity (Youle, R. J. et al. (1994) Proc. Natl. Acad. Sci. USA 91: 6012-6016; Mikulski, S. M. et al. (1990) J. Natl. Cancer Inst. 82: 151-152; and Wu, Y. -N. et al. (1993) J. Biol. Chem. 268: 10686-10693). Angiogenin is a tRNA-specific ribonuclease which binds actin on the surface of endothelial cells for endocytosis. Endocytosed angiogenin is translocated to the nucleus where it promotes endothelial invasiveness required for blood vessel formation (Moroianu, J. and Riordan, J. F. (1994) Proc. Natl. Acad. Sci. USA 91: 1217-1221). Eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are related ribonucleases which possess neurotoxicity (Beintema, J. J. et al. (1988) Biochemistry 27: 4530-4538; Ackerman, S. J. (1993) In Makino, S. and Fukuda, T., Eosinophils: Biological and Clinical Aspects. CRC Press, Boca Raton, Fla., pp 33-74). In addition, ECP exhibits cytotoxic, anti-parasitic, and anti-bacterial activities. A EDN-related ribonuclease, named RNase k6, is shown to express in normal human monocytes and neutrophils, suggesting a role for this ribonuclease in host defense (Rosenberg, H. F. and Dyer, K. D. (1996) Nuc. Acid. Res. 24: 3507-3513).
The discovery of a new human ribonuclease and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of inflammation and disorders associated with cell proliferation and apoptosis.